Despite recent advances in preventing deaths related to cardiac disorders, cardiovascular disease (CVD) remains the leading cause of death in industrialized countries (Thom et al., Circulation 113:e-85-151, 2006). As life expectancy increases, the population profiles in these countries are changing to include increasing numbers of middle-aged and elderly individuals. In both industrialized countries as well as in countries that are becoming industrialized a number of other factors such as altered life styles, urbanization, and as yet unidentified genetic and environmental factors combine to compound the effects of aging on CVD (Lakatta, Heart Fail. Review 7:29-49, 2002). Cardiac arrhythmias are common in patients with cardiac dysfunction and some forms of arrhythmias, such as atrial fibrillations, increase with age (Lakatta and Levy, Circulation 107:346-354). However, the mechanisms underlying arrhythmias and heart failure have remained elusive, in part, because heart diseases in humans are associated with a complex array of hormonal, physiological, genetic and biochemical abnormalities. In addition, vertebrate heart structure is very complex, as is the process of its embryological development from a simple tube-like structure.
Since heart function is so essential for survival, it is difficult to study strongly deleterious heart abnormalities in vertebrate systems. Increasing insights into the molecular genetics of CVD suggest that the genetic heterogeneity underlying heart disease is very high (Priori and Napolitano, Ann. N.Y. Acad. Sci. 1015:96-110, 2004). This aspect of heart disease is difficult to examine in vertebrate systems. The relatively long lifespan of mammalian systems precludes a simple approach to elucidate the aging-related factors contributing to the genesis and facilitation of arrhythmic disorders. More importantly, hereditary and/or acquired arrhythmic disorders in mammalian hearts usually lead to sudden death, making the study of genetic interactions or polygenetic disorders extremely difficult in mammals (Roberts, J. Am. Coll. Card. 47:9-21, 2006). Thus Drosophila, a system that is already a powerful genetic model, provides unique advantages for studying heart aging and disease.
The basic mechanisms of heart development and function are conserved between Drosophila and vertebrates (Bodmer, Trends Cardiovasc. Med. 5:21-27, 1995; Harvey, Dev. Biol. 178:203-216, 1996; Bodmer and Frasch, in Heart Development, eds. Rosenthal and Harvey (Academic Press, New York), pp. 65-90, 1999; Cripps and Olson, Dev. Biol. 246:14-28, 2002; Seidman and Seidman, J. Clin. Investig. 109:451-455, 2002; Bodmer et al., in Comprehensive Insect Science, edited by L. Gilbert, Latrau, K., and Gill S. (Elsevier, Amsterdam, 2005), Vol. 2, pp. 199). We have begun to use the fly heart and the power of Drosophila genetics to understand the genetic and molecular mechanisms underlying aging of cardiac tissue and their contribution to cardiac disorders and arrhythmias.
A number of genetic defects that contribute to arrhythmogenic disorders have been identified in humans. Many of these identified genes encode K+ channels such as the Human Ether-a-go-go Related Gene (HERG), which encodes a channel underlying the rapid phase of cardiac repolarization (IKr), as well as the KCNQ1 gene, which encodes a subunit of a K+ channel responsible for the slower repolarizing current (IKs) (for reviews see Jentsch, Nat. Rev. Neurosci. 1:21-30, 2000; Robbins, Pharmacol. Ther. 90:1-9, 2001; Sanguinetti, Nature 440:463-469, 2006). Mutations in these K+ channels commonly lead to a loss or decrease in channel function resulting in reduced cardiac repolarization and prolonged cardiac action potentials that increase the risk of early after-depolarization (EAD). In humans, this prolonged repolarization phase, which manifests as a prolonged QT interval on the surface electrocardiograms (ECGs), is known as long QT syndrome (LQTS); it is associated with increased risk of Torsades des Pointes (TdP) ventricular arrhythmias, which would cause recurrent syncope or sudden cardiac death. Age, environmental stressors, exercise, genetic modifiers and some commonly prescribed drugs have also been shown to produce arrhythmic disorders such as LQTS, but the complex interactions between these acquired and inherited factors for arrhythmogenesis remain to be determined (Priori and Tristani-Firouzi, Circ, Res. 94:140-145, 2004; Roberts, J. Am. Coll. Card. 47:9-21, 2006).
A systematic genetic analysis will be required to identify genetic variations (polymorphisms) in known genes as well as to identify novel genes and gene products that influence the risk of arrhythmias. Because susceptibility to drug-induced LQTS is likely to have a genetic basis, a functional assessment of genetic mutations and identification of interactions between genes that contribute to arrhythmias would permit more appropriate drug administration to patients with CVD (Grunnet et al., Heart Rhythm 2:1238-1249, 2005).
Thus, there is a need for improved methods and compositions for determining the effects of various genes, and mutations in these genes, on heart function. Moveover, there is a need for improved methods and compositions for screening drugs and other treatments for their effects on heart function. The present invention meets this and other needs.